1H-IMIDAZO{8 1,2a{9 {8 1,4{9 BENZO-DIAZEPINE-1,2(3H)-DIONES

ABSTRACT

This invention relates to 1H-imidazo(1,2-a)(1,4)-benzodiazepine1,2(3H)-diones of the formula WHEREIN R is selected from the group consisting of hydrogen, lower alkyl of 1 through 4 carbon atoms and lower alkenyl of 3 through 4 carbon atoms; R1 is selected from the group consisting of hydrogen and lower alkyl of 1 through 3 carbon atoms; R2 is selected from the group consisting of 2-pyridyl, 3-pyridyl, 4pyridyl, 2-pyrimidyl, furyl, pyrryl, thienyl, lower alkyl of 1 through 3 carbon atoms, lower alkenyl of 2 through 4 carbon atoms, cycloalkyl of 5 through 7 carbon atoms, cycloalkenyl of 5 through 7 carbon atoms and WHEREIN R5 and R6 are selected from the group consisting of hydrogen, lower alkyl of 1 through 3 carbon atoms, halogen, nitro, cyano, trifluoromethyl, lower alkoxy of 1 through 3 carbon atoms, lower alkylthio of 1 through 3 carbon atoms, lower alkylsulfinyl of 1 through 3 carbon atoms, lower alkylsulfonyl of 1 through 3 carbon atoms, lower alkanoylamino having lower alkyl moieties of 1 through 3 carbon atoms and lower dialkylamino having lower alkyl moieties of 1 through 3 carbon atoms; R3 and R4 have the same meaning as R5 and R6, above; and a pharmacologically acceptable acid addition salt thereof. The new products of Formula 1 are useful as sedatives, hypnotics, tranquilizers, muscle relaxants and anti-convulsants in mammals and birds.

United States Patent [191 Moffett Nov. 5, 1974 lH-IMIDAZO[1,2A][1,4]BENZO- DIAZEPlNE-l ,2( 3H )-DIONES Robert B. Moffett, Kalamazoo, Mich.

[73] Assignee: The Upjohn Company, Kalamazoo,

Mich.

221 Filed: May 29,1973

21 Appl. No.: 364,616

Related US. Application Data [63] Continuation-in-part of Ser. No. 195,049, Nov. 2,

1971, abandoned.

[75] Inventor:

[52] US. Cl 260/309.7, 260/239 BD, 260/256.4 R, 260/256.5 R, 260/294.8 C, 260/294.9,

260/295 T, 260/295 K, 260/2955 S, 260/296 B, 260/326.5 CA, 260/326.9, 260/329 S,

[51] int. Cl C07d 57/02 [58] Field of Search 260/309.7, 295 T [56] References Cited OTHER PUBLICATIONS Derieg et al., Chem. Abst., Vol. 69, No. 36092v (l968),QD1.A5l. Derieg et al., Chem. Abst., Vol. 70, No. 878622 (1969),QD1.A51.

Primary ExaminerNatalie T ro us ot' v v M Attorney, Agent, or FirmWillard L. Cheesman; John Kekieh 571 ABSTRACT This invention relates to ll-i-imidazo[1,2-a][l,4]-benzodiazepine-l,2(3H)-diones of the formula wherein R and R are selected from the group con sisting of hydrogen, lower alkyl of I through 3 carbon atoms, halogen, nitro, cyano, trifluoromethyl, lower alkoxy of I through 3 carbon atoms, lower alkylthio of 1 through 3 carbon atoms, lower alkylsulfinyl of I through 3 carbon atoms, lower alkylsulfonyl of 1 through 3 carbon atoms, lower-alkanoylamino having lower alkyl moieties of 1 through 3 carbon atoms and lower dialkylamino having lower alkyl moieties of 1 a through 3 carbon atoms; R and R have the same meaning as R and R above; and a pharmacologically acceptable acid addition salt thereof. The new products of Formula 1 are useful as sedatives, hypnotics, tranquilizers, muscle relaxants and anti-convulsants in mammals and birds.

6 Claims, No Drawings IH-IMIDAZO [1,2A] [1,41BENZO-DIAZEPINE- l,2(3H)-DIONES CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of copending application Ser. No. 195,049, filed Nov. 2, 1971, now abandoned.

BRIEF SUMMARY OF TI-IE INVENTION This invention relates to new benzodiazepines and is particularly concerned with novel lH-,imidazo[l,2- a][ l ,4]-benzodiazepine-l ,2(3H)-diones embraced by the formula 1 3N-R R4 4 i 8 I s R r wherein R, R R R and R have the same meaning as below, and a process for their production. Benzodiazepines having the structure set forth immediately above have not heretofore been reported.

The novel compounds (I) of this invention and a process for their production are represented by the following sequence of formulae wherein R is selected from the group consisting of hydrogen, lower alkyl of 1 through 4 carbon atoms and lower alkenyl of 3 through 4 carbon atoms; R, is selected from the group consisting of hydrogen and lower alkyl of 1 through 3 carbon atoms; R is selected from the group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl, Z-pyrimidyl, furyl, pyrryl, thienyl, lower alkyl of 1 through 3 carbon atoms, lower alkenyl of 2 through 4 carbon atoms, cycloalkyl of 5 through 7 carbon atoms, cycloalkenyl of 5 through 7 carbon atoms and wherein R and R are selected from the group consisting of hydrogen, lower alkyl of I through 3 carbon atoms, halogen, nitro, cyano, trifluoromethyl, lower alkoxy of 1 through 3 carbon atoms, lower alkylthio of 1 through 3 carbon atoms, lower alkylsulfinyl of 1 through 3 carbon atoms, lower alkylsulfonyl of 1 through 3 carbon atoms, lower alkanoylamino having lower alkyl moieties of 1 through 3 carbon atoms and lower dialkylamino having lower alkyl moieties of 1 through 3 carbon atoms; R, and R have the same meaning as R, and R above; X is selected from the group consisting of fluorine, chlorine, and bromine.

Included within the compounds of l are the group in which R is selected from the group consisting of 2- pyridyl, 3-pyridyl, 4-pyridyl and Rs R5 wherein R and R are selected from the group consisting of hydrogen, lower alkyl of 1 through 3 carbon atoms, halogen, nitro, cyano and trifluoromethyl.

The term halogen includes fluorine, chlorine, bromine, and iodine. The term lower alkyl is exemplified by methyl, ethyl, propyl and isopropyl, the term lower alkoxy is exemplified by methoxy, ethoxy, propoxy and isopropoxy. The term lower alkylthio is exemplified by methylthio, ethylthio, propylthio and isopropylthio. The term lower alkylsulfinyl is exemplified by methylsulfinyl, ethylsulfinyl, propylsulfinyl and isopropylsulfinyl. The term lower alkylsulfonyl is exemplified by methylsulfonyl, ethylsulfonyl, propylsulfonyl and isopropylsulfonyl. The term lower alkanoylamino is exemplified by formylamino, acetylamino, propionylamino and isopropionylamino. The term lower dialkylamino is exemplified by dimethylamino, diethylamino, methylethylamino, methylpropylamino, ethylpropylamino, dipropylamino, diisopropylamino and the like. The term lower alkenyl is exemplified by vinyl, l-propenyl, allyl, isopropenyl, methallyl and crotyl. The term cycloalkyl is exemplified by cyclopentyl, cyclohexyl and cycloheptyl. The term cycloalkenyl is exemplified by lcyclopentenyl, l-cyclohexenyl, l-cycloheptenyl, 2- cyclopentenyl, 2-cyclohexenyl, Z-cycloheptenyl, 3-cyclopentenyl, 3-cyclohexenyl, 3-cycloheptenyl and 4-cycloheptenyl.

The novel ll-I-imidazo[l,2-a][1,4]benzodiazepinel,2(3l-I)-diones of Formula I exist either in the nonprotonated (free base) form or in the protonated (acid addition salt) form, depending on the pH of the environment. They form stable protonates, i.e., pharmacologically acceptable acid addition salts, on acidification of the free base with suitable pharmacologically acceptable acids, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, acetic, propionic, palmitic, benzoic, salicylic, hexynoic, phenylbutyric, naphthoic, glycolic, succinic, nicotinic, tartaric, maleic, malic, pamoic, methanesulfonic, cyclohexanesulfonic, cyclohexanesulfonic, citric and lactic acids, and the like. Conversely, the free bases of the novel compounds of Formula I can be obtained from a salt, (e.g., from the hydrochloride or sulfate salt) by neutralization with a base such as sodium hydroxide, extracting with an immiscible solvent, for example chloroform,

drying the extract, for example with anhydrous sodium' sulfate, and removing the solvent by evaporation.

ln carrying out the process for the production of a 1- H-imidazo[ l ,2-a] l ,4lbenzodiazepin-l ,2( 3H )-dione of Formula I of this invention, an appropriate corresponding Z-amino- (alkylamino or alkenylamino)-3l-l- 1,4-benzodiazepine (11) starting material in an inert organic solvent, is mixed in the cold, in the presence of a base, with an oxalyl halide. Suitable inert organic solvents include tetrahydrofuran, dimethylformamide, dioxane, benzene and the like. Suitable bases include 3 pyridine, triethylamine, ethylisopropylamine, dimethylphenylamine, sodium carbonate and the like. Suitable oxalyl halides are oxalyl bromide, oxalyl chloride and oxalyl fluoride. Equimolar quantities of the amino starting material (II) and the oxalyl halide are usually employed, but the reaction is operative with smaller or larger proportions of either reactant. The reaction is carried out at between about 30 to below C., preferably at about 75 C., and usually under an atmosphere of nitrogen. The reaction period is between about several minutes to about 6 hours. The termination of the reaction can be determined by thin layer chromatography, and/or infrared and nuclear magnetic resonance spectra. At the termination of the reaction, the product (I) can be isolated from the reaction mixture by conventional means, for example, when'a water-miscible solvent is used, by pouring the reaction mixture into water and separating the resulting precipitate by filtration or by extraction with water-immiscible solvents. Additional purification of the product can be accomplished by conventional means, for example, by elution chromatography from an adsorbent column with a suitable solvent such as acetone, ethyl acetate, ether, methylene chloride or Skellysolve B (hexanes), mixtures and combination of these solvents;.also by gradient elution chromatography from an adsorbent column with a suitable mixture of solvents, such as methylene chloride-Skellysolve B, acetone-Skellysolve B, and the like.

Starting compounds of Formula 11 wherein R is Rs R and R, R R R R and R have the same meaning as above, can be prepared from the well-known corresponding substituted or unsubstituted-1,3-dihydro-5- (substituted or unsubstituted)phenyl-2H-1,4- benzodiazepines (Ill) (produced in the manner described in J. Org. Chem. 29, 231 and US. Pat. No. 3,422,091) by treatment with ammonia, an alkylamine or alkenylamine in methanol, as set forth herein in Preparation 1' and the paragraphs thereafter.

Appropriate starting materials of Formula [I wherein R is selected from the group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, fury], pyrryl, thienyl, cycloalkyl of'5 through 7 carbon atoms, cycloalkenyl of 5 through 7 carbon atoms and R, R R and R have the same meaning as above, can be prepared by heating known corresponding compounds of the formula wherein R R and R. have the same meaning as above and R has the same meaning as immediately above, with phosphorus pentasulfide in a solvent such as pyridine, benzene, toluene or xylene at between about 80 to about 140 C. for between about 30 minutes to about 6 hours, to yield corresponding substituted or unsubstituted-1,3-dihydro-5substituted-21+ 1,4-benzodiazepine-2-thiones (III), followed by treatment of the thus produced compounds (III) with ammonia, an alkylamine or alkenylamine in methanol, in the manner described herein in Preparations 2 through 5 and the paragraphs following Preparations 3 and 5. The preparation of compounds of Formula IV are described in US. Pat. Nos. 3,100,770; 3,179,656; 3,268,586; 3,338,886; and 3,466,328; Belgian Patents 619,101 and 662,240; French Patents 1,391,752 and 1,455,048; Netherlands Patents 65/07637, 6'7/08966; and J. Pharm. Sci. 53, 264.

The novel compounds of Formula I and the pharmacologically acceptable acid addition salts thereof are central nervous system depressants, having sedative, hypnotic, anticonvulsant, tranquilizing and muscle relaxant effects in mammals and birds.

Substances depressing the central nervous system (CNS) have a variety of manifestations, the mildest being tranquilization. Tranquilizers also cause a state of sedation, hypnosis or indifference in test animals. The first manifestation of depression of the CNS in the mouse is motor weakness (muscle relaxant) and this activity is related to anticonvulsant activity. The general methods used to test for CNS activity are found in chapters 6, 7 and 14 of Turner, Screening Methods in Pharmacology, Academic Press, N.Y., 1965, Volume I Tranquilizing, sedative and hypnotic effects of the compounds of this invention are shown by the following tests in mice:

Chimney test: [Med Exp. 4, (1961)]: This test determines the ability of mice to back up and out of a vertical glass cylinder within 30 seconds. At the effective dosage, 50 percent of the mice fail to do it. Untreated mice almost always back up and out of the cylinder in less than 30 seconds.

Dish test: [G. A. Youngdale, et al., J. Med. Chem. 7, 415 (1964)]: This test is carried out by placing treated mice in glass Petri dishes (5 X 10 cm.) partially embedded in shavings in a standard mouse box. Mice remaining in the dish longer than 4 min. are considered to evidence drug effect. The ED is the dose at which 50 percent of the mice remain in the dish.

Pedestal test: [J. Med. Chem. 7, 415 (1964)]: The untreated mouse will leave a standard pedestal in less than a minute to climb back to the floor of a mouse box. Mice exhibiting tranquilizing, sedative or hypnotic effects will remain on the pedestal in excess of one minute.

Loss of Righting Reflex: [.l. Med. Chem. 1, 281 (1959)]: Groups of 10 mice are injected subcutaneously with the test compound. After 15, 30, 60, 120, 180, 240 and 300 minutes each animal is placed gently on its back on a smooth surface. If the animal remains on its back for 30 seconds, loss of the righting reflex occurs.

Traction: [Med Exptl. 4, 145 (1961 Mice are suspended by means of their forepaws to a metallic wire stretched horizontally. The normal mouse effects a better posture in less than 5 seconds by placing at least one hind paw on the wire. The number of animals incapable of touching the wire with at least one hind paw is noted. At the effective dosage 50 percent of the animals fail to touch the wire with a hind paw.

Ethanol Narcosis: [1. Med. Chem. 13, 23 (1970)]: A

subhypnotic dose of ethanol (5 ml./kg. of a 50 percent aqueous solution) is given orally to groups of six mice 30 minutes after the test compound is given intraperatoneally. Thirty minutes later each mouse is examined for loss of righting reflex.

The following compounds were tested in mice for tranquilizing, sedative and hypnotic effects as shown in the tables below. 8-Chloro-6-(o-chlorophenyl)-ll-l-imidazo-[1,2- a][l,4]benzodiazepine-l,2(3l-l)-dione (A) 8-Chloro-6-phenyl-lll-imidazo-[ l ,2-a][ l ,4]benzodiazepine-l ,2(3H)-dione (B) A (EDS... B (ED...

mg./kg.) mg./kg.) Test Chimney 5.6 22 Dish 0.45 63 .Pedestal 2.8 89 Loss of righting reflex 100 200 Traction 40.0 159 Ethanol Narcosis 4.0 40

Anticonvulsant activity of the compounds of this invention are shown by the following tests in mice.

Electroshock: [1. Med. Chem. 8, 548 (1965)]. This test is a measure of the ability of an anticonvulsant drug to abolish the tonic extensor component in the hind limb of a mouse by the maximal seizure pattern induced by 50 mA of current delivered for 0.2 second. Mice are injected with the test compound intraperitoneally and then challenged with the electric current. The ED is the dose at which 50 percent of the animals do not extend the hind limb after electrical stimulation. Thiosemicarbazide Lethality. [1. Med. Chem. 8, 548 (1965)]. Protection against thiosemicarbazide is a measure of the anticonvulsant effect. The test compound is injected into six mice'immediately prior to injection of thiosemicarbazide mg./kg., intraperitoneally). Protection against letholity 4 hours after thiosemicarbazide is the end point. Pentylenetetrazole. [1. Med. Chem. 14, 1078 (1971- An aqueous solution of pentylenetetrazole (85 mg./kg.) isadministered to a group of 6 mice minutes after the test compound. The mice are then observed for a period of 20 minutes for symptoms of clonic convulsions. The number of animals in each group which were protected against the pentylenetetrazole induced convulsions is used as a quantal response parameter for calculating the effective dose (ED of the test compound. Strychnine Antagonism. [1. Med. Chem. 8, 548 (1965)]. Protection against strychnine lethality is tested by injecting strychnine sulfate 3 mg./kg. i.p., 30 minutes after the test compound. This dose of strychnine is usually always fatal to all of the animals. Lethality is assessed 30 minutes after administration of strychnine.

Nicotine Antagonism. [J. Pharmacol. & Exptl. Therap. 132, 360 (1961)]. Mice are injected with the test compound and 30 minutes later they are injected with nicotine salicylate (2 mg./kg.). Control mice show overstimulation, i.e., (1) running convulsions followed by (2) tonic extensor fits followed by (3) death. The animals are considered pine-l,2(3l-l)-dione (B) A (ED B an' Test mgJkg.) mg./kg.)

Electroshock 200 Thiosemicarbazide 0.18 6.3 Pentylenetetrazole 2.0 50 Strychnine 12.0 100 Nicotine 1.1 63

Myorelaxant or muscle relaxing properties are shown by many agents which exhibit anticonvulsant activity.-

The compounds of this invention also show muscle relaxing properties as evidenced by electroshock, strychnine and nicotine tests performed above The pharmaceutical forms contemplated by this invention include pharmaceutical compositions suited for oral, parenteral and rectal use, e.g., tablets, powder packets, cachets, dragees, capsules, solutions, suspensions, sterile injectable forms, suppositories, bougies, and the like. Suitable diluents or carriers such as carbohydrates (lactose), proteins, lipids, calcium phosphate, cornstarch,,stearic acid, methylcellulose and the like can be used as carriers or for coating purposes. Water and oil, e.g., coconut oil, sesame oil, safflower oil, cottonseed oil, peanut oil can be used for preparing solutions or suspensionsof the active drug. Sweetening,

coloring, and flavoring agents can be added.

For mammals and birds food premixes, with starch, oatmeal, dried fishmeat, fishmeal, flour and the like can be prepared.

As sedatives, hypnotics, anticonvulsants, muscle relaxants and tranquilizers, the compounds of Formula I and their pharmacologically acceptable acid addition salts can be used in dosages of 0.01 mg. to 2.0 mg./kg. in oral or injectable preparations as described above. They can be used to alleviate tension and anxiety in mammals, or birds, e.g., such as occurs when animals are traveling; or to alleviate muscle cramps in pets and domestic animals as occur, for example, after strenuous activity.

DETAILED DESCRIPTION The following preparations and examples are illustrative of the processes and products of the present invention, but are not to be construed as limiting.

PREPARATION l Z-Amino-7-chloro-5-phenyl-3H- l ,4-benzodiazepine A solution of 2,87 g. (10 millimoles) of 7-chloro-l ,3- dihydro-5-phenyl-2H-l ,4-benzodiazepine-2-thione (III) (prepared as in J. Org. Chem., 29, 231) in 50 ml. of methanol saturated with ammonia gas is stirred at 24-26 C. (room temperature) for about 2 1% hours. Crystallization occurs during stirring. The crystals of 2-amino-7-chloro-5-phenyl-3l-l-1,4-benzodiazepine (II) are recovered by filtration and dried, to yield 1.55

l7. 2-amino-6-ethylthio-5-(o-bromophenyl)-3I-I-1,4- benzodiazepine (II),

18. 2-amino-6,8-dichloro-5-(o-fIuorophenyl)-3I-I- l,4-benzodiazepine (II),

19. 2-amino-7-bromo-5-[m-(ethylsulfinyl)phenyl1-8- propoxy-3H-l ,4-benzodiazepine (II),

20. 2-amino-9-diisopropylamino-7-methyl-5-[m- (propylsulfonyl)phenyl]-3H-l,4-benzodiazepine (II),

21. 2-amino-7-bromo-5-(o-fluorophenyl)-3H- l ,4- benzodiazepine (II),

22. 2-amin0-5-(o-fluorophenyl)-3-methyl-3H-l,4- benzodiazepine (II),

23. benzodiazepine (II),

24. 2-amino-5-(p-fluorophenyl)-3-methyl-3I-I-l,4- benzodiazepine (II),

25. 2-amin0-5-(o-chlorophenyl)-7-nitro-3H-1,4- benzodiazepine (II),

26. 2-amino-5-( o-chlorophenyl)-8-nitro-3I-I-I ,4- benzodiazepine (II),

27. 2-amino-7-bromo-5-(o-bromophenyI)-3H-l,4- benzodiazepine (II),

28. 2-amino-5-(o-fluorophenyl)-7-methylsulfinyl- 3H- 1 ,4-benzodiazepine (II),

29. 2-amino-5-(o-chlorophenyl)-5-(o-chlorophenyl(- 7-methyl-3H-l,4-benzodiazepine (II),

30. 2-amino-5-phenyl-7-methylthio-3l-l-1,4- benzodiazepine (II),

31. 2-amino-5-(o-chlorophenyl)-7-cyano-3H-1,4- benzodiazepine (II),

32. 2-amino-5-(o-chlorophenyl)-3,6,8-trimethyl-3H- 1,4-benzodiazepine (II),

33. 2-amino-7-methyl-5-phenyl-9-propylsulfonyl-3H- l,4-benzodiazepine (II),

34. 2-amino-S-(o-chlorophenyl)-7-trifluoromethyl- 3l-I-l ,4-benzodiazepine (II),

35. 2-amin0-7-dimethyIamino-5-phenyl-3l-l-I,4- benzodiazepine (II),

36. 2-amino-5-(o-chlorophenyl )-7-fluoro-3H- l ,4- benzodiazepine (ll),

37. 2-amino-7,8-dicyano-5-[p- (methylsulfonyl)phenyl]-3H-l,4-benzodiazepine (ll),

38. 2-amino-6,9-dichloro-5-(p-isopropylphenyl)-3H- 1,4-benzodiazepine (ll),

39. 2-amino-6,8-diethyl-5-(m-ethylphenyI)-3H-l,4- benzodiazepine (ll),

40. 2-amino-5-(o-cyanophenyl)-6-nitro-3H-l ,4- benzodiazepine (II),

41. 2-amino-7,9-bis(dipropylamino)-5-(onitrophenyI)-3l-l-l,4-benzodiazepine (ll),

42. 9-acetylamino-2-amino-5-(p-cyanophenyl)-3H- 1,4-benzodiazepine (II), and the like.

Following the procedure of Preparation I but substituting other representative l,3-dihydro-2l-l-l,4-benzodiazepine-Z-thiones (III) as starting materials and substituting an alkylamine or alkenylamine for ammonia, such as l. 7-chloro-l ,3-dihydro--phenyl-2H-1,4-benzodiazepine-Z-thione (III) and methylamine,

2. 1,3-dihydro-3-ethyI-7-fluoro-5-(p-fluorophenyl)- 2I-l-l,4-benzodiazepine-2-thione (III) and ethylamine,

3. l,3-dihydro-7-nitro-5-[p- (trifluoromethyl)phenyll-Zl-ll ,4-benzodiazepine-2- thione (III) and propylamine,

4. 7-chloro-1,3-dihydro9-fluoro-5-(mmethoxyphenyl )-2I-I-l ,4-ben zodiazepine-Z-thione (III) and isopropylamine,

5. l,3-dihydro-8-ethylthio-5-(p-propyIphenyU-ZH- 1,4-benzodiazepine-2-thione (III) and butylamine,

6. 7-chloro- I ,3-dihydro-9-ethoxy-3-methyl-5-[ p- (methylsulfinyl)phenyll-ZH- l ,4-benzodiazepine-2- thione (III) and allylamine,

7. 8-diethylamino- I ,3-dihydro-9-ethylthio-5-phenyl- 2H- 1 ,4-benzodiazepine-2-thione (III) and I methylallylamine,

8. 7,8-dibromo-l,3-dihydro-9-propionylamino-5-(2- propoxy-4-propylphenyl)-2H-l ,4-benzodiazepine-2- thione (III) and 2-methylallylamine,

9. l,3-dihydro-9-nitro-5-[p- (propionylamino )phenyI]-2H- l ,4-benzodiazepine-2- thione (III) and ethylallylamine,

l0. 7-chloro-8-diethylamino-5-(2,6-difluorophenyl)- I,3-dihydro-2H-l,4-benzodiazepine-2-thione (III) and crotyIamine (i.e., l-amino-Z-butene), and the like, yields, respectively,

I. 7-chloro-2-(methylamino)-5-phenyl-3l-l- I ,4- benzodiazepine (II),

2. 3-ethyl-2-(ethylamino)-7-fluoro-5-(pfluorophenyI)-3H-l,4-benzodiazepine (III),

3. 7-nitro-2-(propylamino)-5-[p-(trifluoromethyl)- phenyl]-3I-l-1,4-benzodiazepine (II),

4. 7-chloro-9-Iluoro-2-(isopropylamino)-5-(mmethoxyphenyl)-3l-I-l ,4-benzodiazepine (II),

5. 2-(butylamino)-8-ethylthio-5-(p-propylphenyl)- 3H-l,4-benzodiazepine (II),

6. 2-(allylamino)-7-chloro-9-ethoxy-3-methyl-5-[p- (methylsulfinyl)phenyl]-3I-I-I,4-benzodiazepine (II),

7. 8-diethylamino-9-ethyIthio-2-( 1- methylallylamino)-5-phenyl-3l-ll ,4-benzodiazepine 8. 7,8-dibromo-2-(2-methylallylamino)-9- propionylamino-5-(2-propoxy-4-propylphenyl)-3H- 1,4-benzodiazepine (II),

2-(ethylallylamino)-9-nitro-5-[p- (propionylamino)-phenyl]-3H- I ,4-benzodiazepine 10. 7-chloro-2-(crotylamino)-8-diethylamino-5-(2,6- difluorophenyl)-3H-I,4-benzodiazepine (II), and the like.

PREPARATION 2 7-bromo-1,3-dihydro-5-(2-pyridyI)-2H-l ,4-benzodiazepine-Z-thione (III) A stirred solution of 6.53 g. of 7-bromo-l ,3-dihydro- 5-(2-pyridyl)-2I-l-l,4-benzodiazepin-2-one (IV) (prepared as in J. Pharm. Sci. 53, 264) in 400 ml. of dry pyridine is heated in an oil bath, under nitrogen, with 5.05 g. of phosphorus pentasulfide at between about to C. for about 1 hour, cooled and concentrated under vacuum. Pyridine remaining in the residue is removed by the successive addition of xylene and toluene with vacuum concentration after each addition of solvent. The dark brown solid residue is triturated with a mixture of aqueous sodium carbonate solution and chloroform and the resulting finely divided tan solid is collected by filtration, washed with water, dissolved in a mixture of chloroform and ethanol, decolorized with activated carbon and crystallized to yield 3.39 g. of product melting at 249 C. (with decomposition); and 0.559 g. melting at 243 C. (with decomposition). The analytical sample is crystallized from ethanol to give Anal. Calcd. for C l-l BrN s: C, 50.61; H 3.03; Br, 24.06; N, 12.65;

C, 49.82; H, 3,31; Br, 24.31; N, 12.60; s 9.59

Found:

PREPARATION 3 7-chloro-l ,3-dihydro--methy1-2I-I-1,4-benzodiazepine-Z-thione (III) To a hot solution of 1 g. (5mmoles) of 7-ch1oro-1,3- dihydro-S-methyl-ZH-l ,4-benzodiazepin-2-one (IV) (prepared as in French Patent 1,391,752) in 150 ml. of xylene, 1.1 g. (Smmoles) of phosphorus pentasulfide is added. The mixture is heated underreflux in a nitrogen atmosphere for about 4 hours. The reaction mixture is cooled and filtered, with the filtrate containing only a small amount of material. The filtered solid is treated with hot water and filtered again.'The filtrate is treated with percent sodium hydroxide to give a pH of 6 to 8 and the white solid removed by extraction with ethyl acetate to give 129 mg. of crude product. The initial solid is again treated with water, the. aqueous phase made basic with sodium, bicarbonate and then extracted with hot ethyl acetate to give 1 g. of brown solid. This material plus the 129 mg. of crude product are chromatographed on 130 g. of silica gel using 50 percent ethyl acetate: 50 percent cyclohexane as eluting solvent. The product .taken from the column is recrystallized from ethyl acetate to give 455 mg. of product, having a melting point of 205 to 206 C. (with decomposition). A previously prepared sample of the product, 7-chloro-l ,3-dihydro-5-methyl-2H-l ,4-benzodiazepine-2-thione, melts at 201 to 203 C. and gives the analysis that follows.

Anal. Calcd. for C, H CIN,S: C, 53.45; H 4.04;

S. 14.27. Found: C, 53.29; H, 3.87; N, 12.16; Cl, 15.88;

Following the procedure of Preparations 2 and 3 but substituting other known representative 2I-I-1,4- benzodiazepin-Z-ones (1V) such as 7-bromo l ,3-dihydro-5-ethy1-2H- 1 ,4- benzodiazepin-Z-one (IV),

2. 1,3-dihydro-7-nitro-5-propy1-2l-I-1,4- benzodiazepin-Z-one (IV), I 1 1 3. '1,3-dihydro-3-methy1-5-(2-pyridy1)-2I-I-l,4- benzodiazepin-Z-one (IV),

4. l',3-dihydro-7-.fluoro-5-(4-pyridyl)-2I-I-1,4- benzodiazepin-Z-one (1V),

5. 7-ch1oro-1,3-dihydro-3-propyl-5-(3-pyridy1)-2I'I- 1,4-benzodiazepin-2-one (IV),

6. 1,3-dihydro-5-(2-pyridyl)-7-trifluoromethyl-2I-1- 1,4-benzodiazepin-2-one (IV),

7. 3-ethyI-1,3-dihydro-5-(4-pyridyl) 7- trifluoromethyl-2H-1,4-benzodiazepin-2-one (IV),

8. l ,3-dihydro-3-propyl-5-( 2-pyridy1)'-7- trifluoromethyl-2H- l ,4-benzodiazepin-2-one (IV),

9. 1,3-dihydro-7-methylthio-5-(2-pyridyl)-2I-I-1,4- benzodiazepin-Z-one (IV),

10. 1,3-dihydro-5-(3-pyridy1)-7-trifluoromethy1-2H- l,4-benzodiazepin-2-one (IV),

1 l. 7-bromo-1,3-dihydro-5-(2-pyridy1)-8-nitro-2H- 1,4-benzodiazepin-2-one (IV),

12. 7-chloro-1,3-dihydro-5-(3-pyridy1)-9- trifluoromethyl-ZH-l,4-benzodiazepin-2-one (IV),

13. 7-fluoro-l,3-dihydro-3-propy1-5-(4-pyridy1)-8- trifluoromethyl-ZI-I- l ,4-benzodiazepin-2-one (IV),

14. 1,3-dihydro-5-(2-pyridy1)-2I-I- l ,4-benzodiazepin- 2-one (IV),

l5. 1,3-dihydro-7-iodo-9-nitro-5-(3-pyridyl)-2I-I-1,4- benzodiazepin-Z-one (IV),

16. 7-chloro-1,3-dihydro-5-(2-pyridyl)-2I-I-1,4- beh zodiazepin-Z-one (IV), 17. 1,3-dihydro-7-nitro-5- (2-pyridyl)-2H-1,4-benzodiazepin-2-one (IV),

18. 7-bromo-l ,3-dihydro-9-methyl-5-( 2-pyridyl)-2I-I- 1,4-benzodiazepin-2-one (IV),

19. 7-bromo-1,3-dihydro-3-methy1-5-(2-pyridyl)-2I-I- 1,4-benzodiazepin-2-one (IV),

20. 7-chloro-l,3-dihydro-3-ethyl-5-(4-pyridyl)-2l-I- 1,4-benzodiazepin-2-one (IV),

21. 7-bromo-1,3-dihydro-3-methyl-5-(4-pyridyl)-2H- 1,4-benzodiazepin-2-one (IV),

22. l,3-dihydro-7-fluoro-3-propyl-5-(4-pyridyl)-2l-I- 1,4-.benzodiazepin-2-one (IV),

23. 7-ch1oro-l,3-dihydro-5-(2-pyrryl)-2I-I-1,4- benzodiazepin-2-one (IV),

24. l,3-dihydro-5-(2-pyrryl)-2H-1,4-benzodiazepin- 2-one (IV),

25. l,31dihydro-7-nitro-5-(2-thienyl)-2H-1,4 benzodiazepin-Z-one (IV),

26. 1,3-dihydro-9-rnethoxy-5-(2-thienyl)-2H-1,4- benzodiazepin-Z-one (IV),

27. 7-chloro-l ,3-dihydro-5-( 2-thienyl )-2H-l ,4- benzodiazepin-2-one (IV),

28. 7-br'omo-l ,3-dihydro-8-ethyl-5-(2-thieny1)-2I-I- 1,4-benzodiazepin-2-one (IV),

29; 7-ch1oro-1,3-dihydro-9-propyl-5-(2-thienyl)-2l-I- 1,4-benzodiazepin-2-one (IV),

30. 7-diethylamino-1,3-dihydro-5-(2-pyridyl)-2H- 1,4-benzodiazepin-2-one (IV), 1

31. l,3-dihydro-9-methylthio-7-nitro-5-( 2-pyridyl 2l-I-l',4-benzodiazepin-2-one (IV),

32. 7-bromo-8-fluoro-1,3-dihydro-5-(2-pyridyl)-2I-I- 1,4-benzodiazepin-2-on (IV),

33. 7-ch1oro-1,3-dihydro-8-ethoxy-5-(2-pyridyl)-2I-I- 1,4-benzodiazepin-2-one (IV),

34. 1,3-dihydro-5-(4-pyridy1)-2I-1-1,4-benzodiazepin- 2-one (IV),

35. 7-bromo-1,3-dihydro-5-(4-pyridyl)-21-1-1 ,4- benzodiazepin-Z-one (IV),

36. l,3-dihydro-7-nitro-5-(4-pyridyl)-2l-l-l ,4- benzodiazepin-Z-one (IV),

37. 7-chloro-1,3-dihydro-9-ethy1-5-(4-pyridyl)-2I-I- 1,4-benzodiazepin-2-one (IV),

38. l ,3-dihydro-7-methy1-5-(4-pyridyl)-21-I-1 ,4- benzodiazepin-Z-one (IV),

39. 7-bromo-l,3-dihydro-8-ethyl-5-(4-pyr1dyl)-2H- 1,4-benzodiazepin-2-one (IV),

40. 7-ch1oro-1,3-dihydro-9-propyl-S-(4-pyridyl)-2l-I- 1,4-benzodiazepin-2-one (1V),

35. benzodiazepine (ll),

36. 2-amino-5-(2-pyrimidyl)-3H-l,4-benzodiazepine 37. benzodiazepine (II),

3 8. 2-amino-9-fluoro-5-( 2-pyrryl )-3H- 1 ,4- benzodiazepine (II),

39. 2-amino-3-ethyl-7-fluoro-5-( 2-furyl)-3H- l ,4- benzodiazepine (II),

40. 2-amino-7-bromo-8-chloro-5-cyclopentyl-3H- 1,4-benzodiazepine (II),

41. 2-amino-8-bromo-5cyclopentyl-7- trifluoromethyl-3H-l,4-benzodiazepine (ll),

42. 2-amino-7-bromo-5-cyclohexyl-7-nitro-3H-1,4 benzodiazepine (II),

43. 2-amino-8-bromo-5cycloheptyl-3H-1,4- benzodiazepine (II),

I 44. 2-amino-7-chloro-5-isopropenyl-3-methyl-3H- 1,4-benzodiazepine (II),

45. 2-amino-8chloro-3ethyl-7-nitro-5-(4-pyridyl)- 3l-l-l,4-benzodiazepine (ll),

46. 2-amino-7-bromo-5-(2-furyl)-3H-1,4- benzodiazepine (ll),

47. 2-amino-7-bromo-5-( 1-cyclohexenyl)-9- trifluoromethyl 3H-l,4-benzodiazepine (II),

48. 2-amino-3,5dimethyl-7-propoxy-3H-1,4 benzodiazepine (II),

49. 2-amino-3-ethyl-51propyl-8-trifluoromethyl-3H- 1,4-benzodiazepine (II),

50. 2-amino-7,9-dichloro-3-ethyl-5-(2-thienyl)-3H- 1,4-benzodiazepine (I1), and the like.

Following the procedure of Preparation 1 but substituting other representative l,3-dihydro-2H-l,4-benzodiazepine-2-thiones (lIl) (obtained as in Preparations 2 through 5 and the paragraph following Preparation 3) as starting materials, and substituting an alkylamine or alkenylamine for ammonia, such as 1. 7-bromo-1,3-dihydro-5-(2-pyridyl)-2l-l-1,4-benzodiazepine-Z-thione (III) and methylamine,

2. 7-chloro-1,3-dihydro-5-methyl-2l-I-l,4benzodiazepine-2-thione (Ill) and ethylamine,

3. 1,3dihydro-3-ethyl-7-f1u0ro-5-(2-furyl)-9- trifluoromethyl-2H-1,4benzodiazepine-2-thione (Ill) and propylamine,

4. 1 ,3dihydro-9-methyl-5-(2-pyrryl)-2I-l-1,4-benzodiazepine-Z-thione (III), and isopropylamine,

5. 7-bromo-l ,3-dihydro-9-nitro-5-( 2-thienyl)-2I-l- 1,4-benzodiazepine-Z-thione (Ill) and butylamine,

6. 1,3dihydro-7-ethylthio-9-fluoro-5-(2-pyrimidy1)- 2H-1,4-benzodiazepine-2-thione (III) and isobutylamine,

7. 7-chloro-1,3dihydro-8-methoxy-5-propyl-2H-1,4- benzodiazepine-Z-thione (II) and allylamine,

8. 8-acetylamino-7-bromo-5-(3-pyridyl)-2H-1,4-benzodiazepine-Z-thione (III) and l-methylallylamine,

9. 8bromo-9-chloro-5-cyclohexyl-2H-1,4-benzodiazepine-Z-thione (Ill) and 2-methylallylamine,

10. 5-cyclopentyl-1,3dihydro-7-dimethylamino-8- fluoro-3-propyl-2l-l-1,4-benzodiazepine-Z-thione (Ill) and allylamine,

1 l. 8-bromo-5-(1-cyclohexenyl)-1,3-dihydro-7- nitro-ZH-l,4-benzodiazepine-2-thione (III) and 2- methylallylamine,

12. 9-chloro-8-cyano-5-( 2-cycloheptenyl)-7- ethylsulfonyl-2H-1,4-benzodiazepine-2-thione (III) and crotylamine,

2-amino-8-bromo-5-(4-pyridyl)-3l-l-1,4-

Y and the like, yields, respectively,

1. 7-bromo-2-(methylamino)-5-(2pyridyl)-3I-l-1,4- benzodiazepine (II),

2. 7-ch1oro-2-(ethylamino)'5-methyl-3H-l ,4-

2-amino-7-ch1oro-5methyl-3H-l,4- 5 benzodiazepine (II),

3. 3-ethyl-7-fluoro-5-(2-furyl)-2-(propylamino)-9- trifluoromethyl-3H- 1 ,4-benzodiazepine (II 4. 2-(isopropylamino)-9-methyl-5-(2-pyrryl)-3H- 1,4-benzodiazepine (I1),

5. 7-bromo-2-( butylamino )-9-nitro-5-( 2-thienyl 3I-I-l ,4-benzodiazepine (I1),

6. 7-ethylthio-9-fluoro-2-(isobutylamino)-5-(2- pyrimidy1)-3H-l ,4-benzodiazepine (ll),

7. 2-(allylamino)-7-chloro-8methoxy-5-propyl-3H- 1,4-benzodiazepine (II),

8. 8-acetylamino-7-bromo-2-(l-methylallylamino)- 5-(3-pyridy1)-3H-l,4-benzodiazepine (ll),

9. 8bromo-9-chloro-5-cyclohexyl-2-(2- methylallylamino )-3H- 1 ,4-benzodiazepine (II 10. 5cyclopentyl-7-dimethylamino-5-( allylamino 8-fluoro-3-propy1-3Hl ,4-benzodiazepine (ll),

1 l. 8-bromo-5-( l-cyclohexenyl)-2-(2- methylallylamino)-7-nitro-3H-1 ,4-benzodiazepine (II),

12. 9-chloro-2-(crotylamino)-8-cyano-5-(2- cycloheptenyl)-7-ethylsulfonyl-3H- l ,4-benzodiazepine (II), and the like.

EXAMPLE 1 8-chloro-6-phenyl-1l-l-imidazo[1,2-a][ 1,4]benzodiazepine-l,2(3H)-dione (l) A filtered solution of 5.38 g. (0.02 mole of 2-amino- 7-ch1oro-5-pheny1-3l-l-l,4-benzodiazepine (ll) (prepared as in Preparation 1) and 4.03 ml. (0.05 of dry pyridine in 200 ml. of tetrahydrofuran is cooled to about 76 C. under nitrogen by a mixture of solid carbon dioxide and chloroform. Then 2.05 ml. (3.05 g.; 0.024 mole) of oxalyl chloride is slowly added with stirring during a period of about 10 minutes. Solid material separates immediately and after stirring for about 4 hours at about 76 C., the mixture is allowed to warm to room temperature and then stirringcontinued for about 19 hours. The brown mixture is concentrated under vacuum at below 30 C.'and mixed with ice water. The mixture is well shaken with chloroform leaving orange solid insoluble material in both layers. This material is collected, washed with water, then methylene chloride and dried to give 3.15 g. of orange solid. This is recrystallized from ml. of tetrahydrofuran to give 2.53 g. of orange crystals, which on drying at 100 C./under 0.1 mm. Hg. for about 3 hours has a melting point of 226 to 245 C. after sintering at about C. This material is shown by its nmr (nuclear magnetic resonance) spectrum and melt solvate to contain about A: mole of tetrahydrofuran. Infrared, ultraviolet, nmr and mass spectral data confirm the structure predicted for the compound, 8-chloro-6-phenyl-1H-imidazo[1,2- a][1,4]benzodiazepine-l,2(3H)-dione tetrahydrofuran solvate (3:1) (1).

N, 12.08; THF, 6.92v

Found: C, 63.41; H, 3.64; Cl, 10.37;

N, 12.34; THF (melt solvate) 7.37.

Anal. Calcd. for C H ClN o z C, 63.07; H, 311; C1, 10.95; N, 12.98.

Found: C, 62.74; H, 3.15;

EXAMPLE 2 8-chloro-3-methyl-6-phenyl-lH-imidazo[1,2-a]- [1,4lbenzodiazepine-1,2(3H)-dione (l) A mixture of 2.02 ml. (0.025 mole) of dry pyridine, 25 ml. of tetrahydrofuran and 1.03 ml. (1.53 g.) ofoxalyl chloride is cooled to about 76 C. by a mixture of solid carbon dioxide and acetone, and a solution of 2.84 g. (0.01 mole) of 7-chloro-2-(methylamino)-5- phenyl-3H-l,4-benzodiazepine (11) ]prepared as in J. Org. Chem. 29, 231; or, as in the second paragraph following Preparation 1, above, wherein it is the compound of Formula 11 designated (1)] in 100 ml. of tetrahydrofuran is added dropwise under nitrogen with stirring during a period of about 1.5 hours. After stirring at about 76 C. for about 0.5 hour more, the mixture is allowed to warm to room temperature and is stirred for about hours. After standing in the refrigerator for about 16 hours, the mixture is evaporated under vacuum to give an orange solid which is well shaken with water and ether. The solid is collected, washed with water and ether-and dried to give 2.87 g. of orange solid. This is recrystallized from 125 ml. of n-butanol (being filtered while hot) to give 2.09 g. (61 percent yield) of orange leaflets of 8-chloro-3-methyl-6-phenyllH-imidazo[ 1,2-a][ l,4]-benzodiazepine-l,2(3H)- dione (1), having a melting point of 203 to 204.5 C. Infrared, ultraviolet, nmr and mass spectral data confirm the structure predicted for the compound.

Anal. Calcd. for C H CIN O C, 64.01; H, 3.58; Cl, 10.50; N, 12.14.

Found: C, 64.11; H, 3.58;

CI, 10.53; N, 12.67.

EXAMPLE 3 8-chloro-6-(o-chlorophenyl)-lH-imidazo[1,2- a][1,4]benzodiazepine-1,2(3H)-dione (I) A suspension of 3.04 g. (0.01 mole) of 2-amino-7- chloro-5-(o-chlorophenyl)-3H-1,4-benzodiazepine (11) [prepared as in the first paragraph following Preparation 1, above, wherein it is the compound of Formula 11 designated (16)] in 100 ml. of tetrahydrofuran is cooled under nitrogen to about 76 C. by a mixture of solid carbon dioxide and acetone, and 2 ml. (0.025 mole) of dry pyridine is added. Then 1 ml. (0.012 mole) of oxalyl chloride is added dropwise with stirring during a period of about 10 minutes. After stirring under nitrogen for about 3.5 hours the mixture is allowed to warm to room temperature and stirring is continued for about 17 hours. The mixture is evaporated to dryness under vacuum at about 40 Cfand the residue shaken well with ice water and methylene chloride. The pH is adjusted to 6 with ammonium hydroxide and acetic acid and extracted well with methylene chloride. The methylene chloride solution is washed with water and evaporated to dryness. The residue is dissolved in tetrahydrofuran, boiled with activated carbon, filtered, and evaporated to dryness under vacuum. Boiling this residue with 45 ml. of chloroform gives a solid, which after cooling, is collected, washed with chloroform and ether, and dried to give 0.84 g. of orange-yellow solid. This is dissolved in ml. of isopropanol, the solution filtered hot, concentrated and cooled to give 0.53 g. (13.7 percent yield) of orange-yellow solid melting at 230 to 250 C. after sintering and foaming at 169 to 175 C. Nmr data confirms the structure proposed for the compound, 8-chloro-6-(o-chlorophenyl)-1H- imidazo[ l ,2-a] 1,4]benz0diazepine- 1 ,2( 3H )-di0ne isopropanol solvate (2:1) (1), showing about 1/2 molecule of isopropanol/molecule. Infrared and ultraviolet spectra are also in agreement with the predicted structure of the compound.

Anal. Calcd. for C, H Cl N O H O:

C, 57.24; H, 3.37; C1, 1826; N, 10.82. Found: C, 56.24; H, 3.46; Cl, 18.17;

Heating the thus produced compound in a vacuum oven at 0.1 mm. Hg at C. for 1 hour gives the anhydrous compound, 8-chloro-6-(ochlorophenyl)-1H- imidazo[l,2-a][1,4]-benzodiazepine-1,2(3H)-dione (1).

Following the procedure of Examples 1, 2 and 3 but substituting other representative 2-amino(alkylamino or alkenylamino)-5-substituted-3H-1,4- benzodiazepines (11) as starting materials, such as l. 2-amino-5(m-bromophenyl)-7-chloro-3H-1,4- benzodiazepine (11),

2. 2-amino-3,6,8-triethyl-5-[m-(trifluoromethyl)- phenyll-3H-1,4-benzodiazepine (l1),

3. 2-amino-7,8-dicyano-5-[p- (methylsulfinyl)phenyl]-3H-l,4-benzodiazepine (11),

4. 2-amino-7-methylthio-5-phenyl-3H-1,4- benzodiazepine (ll),

5. 2-amino-6-chloro-5-(2,5-dimethoxyphenyl)-3H- 1,4-benzodiazepine (l1),

6. 2-amino-3,6-dipropyl-5-(m-propylphenyl)-3H- 1,4benzodiazepine (11),

7. 2-amino-5-(o-cyanophenyl)-7,9- bis(diethylamino)-3H-l ,4-benzodiazepine (11),

8. 2-amino-8-acetylamino-5-(p-nitrophenyl)-3H-l ,4- benzodiazepine (ll),

9. 2-amino-6,8-dibromo-5-(misopropylphenyl)-3H- 1,4-benzodiazepine (ll),

10. 2-amino-8-ethylsulfonyl-7-methyl-5-phenyl-3H- l,4-benzodiazepine (11),

l l. 2-amino-5-(o-chlorophenyl)-7-iodo-3H-1,4- benzodiazepine (11),

12. 2-amino-7-bromo-5-(2,5-difluorophenyl)-3H- l,4-benzodiazepine (l1),

6-cyelohexyl-9-diethylamino3-allyl-4-propyll,2-a][ l ,4]benzodiazepinel ,2(3H)- wherein R is selected from the group consisting of hy drogen, lower alkyl of I through 4 carbon atoms and lower alkenyl of 3 through 4 carbon atoms; R, is seleeted from the group consisting of hydrogen and lower alkyl of I through 3 carbon atoms; R is selected from the group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl and a Rn Rs wherein R and R are selected from the group consisting of hydrogen, lower alkyl of 1 through 3 carbon atoms, halogen, nitro, cyano and trifluoromethyl; R and R, have the same meaning as R and R above; or a pharmaeologically acceptable addition salt thereof.

2. A compound of claim 1 wherein R, R, and R, are hydrogen, R is wherein R and R are hydrogen and R is 8-chloro,

32 namely, 8-chloro-6-phenyl-lH-imidazo[1,2-a]- [l,4]benzodiaZepine-l ,2( 3H )-dione.

3. A tetrahydrofuran solvate of a compound of claim 1 wherein R, R, and R, are hydrogen, R is wherein R and R are hydrogen and R is 8-ehloro, namely, 8-ehloro-- -phenyl-phenyl-1H-imidazo[l,2-a][1,4lbenzodiazepine-l ,2(3H)-dione tetrahydrofuran solvate.

4. A compound of claim 1 wherein R is methyl, R, and R, are hydrogen, R is I wherein R and R are hydrogen and R is 8-ehloro, namely, 8-ehloro-3-methyl-6-phenyl-I H-imidazo[ l ,2- a][ l,4]benzodiazepine-l ,2( 3H)-dione.

5. A compound of claim 1 wherein R, R, and R, are hydrogen, R is XX R5 R5 wherein R is hydrogen and R is o-chloro, and R is 8-chl0ro, namely, 8-chloro-6-(o-ehlorophenyl)-1H- imidazo[1,2-a][ l ,4]benzodiazepine-l ,2( 3H)-di0ne.

6. An isopropyl alcohol solvate of a compound of claim 1 wherein R, and R, and R are hydrogen, R is XX R0 R5,

wherein R is hydrogen and R is o-chloro, and R is 8- ehloro, namely, 8-chloro-6-(o-chlorophenyl)-1H- imidazo[ l,2-a][1,4]b'en2odiazepine-1,2(3H)-dione isopropyl alcohol solvate. 

1. A COMPOUND OF THE FORMULA
 2. A compound of claim 1 wherein R, R1 and R4 are hydrogen, R2 is
 3. A tetrahydrofuran solvate of a compound of claim 1 wherein R, R1 and R4 are hydrogen, R2 is
 4. A compound of claim 1 wherein R is methyl, R1 and R4 are hydrogen, R2 is
 5. A compound of claim 1 wherein R, R1 and R4 are hydrogen, R2 is
 6. An isopropyl alcohol solvate of a compound of claim 1 wherein R, and R1 and R4 are hydrogen, R2 is 